GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis

The non-receptor tyrosine kinase Src is a major player in multiple physiological responses including growth, survival and differentiation. Overexpression and/or oncogenic mutation in the Src gene have been documented in human tumors. The v-Src protein is an oncogenic mutant of Src, which promotes cell survival, migration, invasion and division. GRIM-19 is an anti-oncogene isolated using a genome-wide knockdown screen. GRIM-19 binds to transcription factor STAT3 and ablates its pro-oncogenic effects while v-Src activates STAT3 to promote its oncogenic effects. However, we found that GRIM-19 inhibits the pro-oncogenic effects of v-Src independently of STAT3. Here, we report the identification of functionally inactivating GRIM-19 mutations in a set of Head and Neck cancer patients. While wild-type GRIM-19 strongly ablated v-Src-induced cell migration, cytoskeletal remodeling and tumor metastasis, the tumor-derived mutants (L(71)P, L(91)P and A(95)T) did not. These mutants were also incapable of inhibiting the drug resistance of v-Src-transformed cells. v-Src down regulated the expression of Pag1, a lipid raft-associated inhibitor of Src, which was restored by wild-type GRIM-19. The tumor-derived mutant GRIM-19 proteins failed to upregulate Pag1. These studies show a novel mechanism that deregulates Src activity in cancer cells.